BioWorld International Correspondent

LONDON - A team of French physicians said it has proof of principle that autologous cell therapy is a viable treatment for myocardial infarction. A post-mortem study carried out on one of 10 patients who received the experimental treatment showed that the grafted cells survived in the heart, and that they started to make a type of muscle protein that is made by heart muscle.

This report gives further encouragement to the team, which already has embarked on a Phase II study of the treatment. The Phase II study is being run jointly by Genzyme Biosurgery, a subsidiary of Genzyme Corp. in Cambridge, Mass., the biotechnology company Myosix SA in Paris, and the Assistance Publique Hopitaux de Paris. (See BioWorld International, July 31, 2002).

Albert Hagege, professor of cardiology at the Hospital European Georges Pompidou in Paris, told BioWorld International, "These results have allowed us for the first time to prove that the concept of putting skeletal muscle cells into heart muscle actually works in practice."

Hagege, together with collaborators based at hospitals throughout Paris, reports the latest findings in a Feb. 8, 2003, Research Letter to The Lancet titled "Viability and differentiation of autologous skeletal myoblast grafts in ischaemic cardiomyopathy."

Hagege said he was not surprised by the outcome of the study because many animal experiments carried out by the team had suggested that skeletal muscle cells could survive in the heart. But, he added, "many people over the years have told us that these cells could not survive in the fibrotic non-vascularized regions of the heart where we placed them, and these people are now surprised by these results."

The therapy involves removing skeletal stem cells called myoblasts from one of the patient's own leg muscles, culturing the cells to increase their number, and injecting them into the damaged myocardium following myocardial infarction.

As part of a Phase I trial carried out during 2000 and 2001, 10 patients underwent this procedure while also undergoing coronary artery bypass grafting. One patient died almost immediately. The results reported in The Lancet relate to a patient belonging to this original group, who survived the procedure for almost 18 months before dying from a stroke.

Tests carried out on the heart muscle of this 72-year-old man showed that the region that had been injected with the myoblasts contained islets of adult skeletal muscle cells (myotubes) embedded in fibrotic heart muscle. There was no associated inflammation, and no growth of new blood vessels.

These muscle cells looked histologically normal for skeletal muscle, and experiments showed that they had cell marker proteins normally found on skeletal muscle, and that cell marker proteins that are normally found on cardiac muscle were absent.

Hagege said, "All muscle cells produce the protein myosin, but there are two isoforms of myosin, the fast form, which is found predominantly in skeletal muscle, and the slow form, which is found predominantly in cardiac muscle, which, as you would expect, is the form of the protein that is best for the type of work the heart muscle does. When we looked at the grafted cells, we found that they expressed a lot of the slow isoform of myosin."

Analysis showed that 35 percent of the grafted myotubes expressed only the fast isoform of myosin, 32 percent only the slow isoform and 33 percent expressed both isoforms. By contrast, analysis of a biopsy of the skeletal muscle from which the graft was taken had earlier shown that 55 percent of the fibers expressed the fast isoform of myosin, 44 percent the slow isoform and 0.6 percent both.

These findings allow three conclusions, Hagege told BioWorld International. "We can now say that the graft is still live, 18 months later, and that it probably contributes to the improvement in the patient's heart function, and that there is some change in the phenotype of the cells in their new environment."

He said that because all 10 patients in the trial had also undergone coronary artery bypass grafts at the same time as the cell therapy, it was difficult to tell to what extent the observed improvement in the function of their hearts was due to the bypass procedures and what was due to cell therapy. However, the Phase II trial is designed to answer that question. The 300 patients who take part will be randomized to receive either a placebo injection or an injection of their own skeletal muscle cells during the bypass procedure.

Hagege and his colleagues also are continuing with animal studies to try to find out whether the grafted cells themselves contract or whether they increase contraction of surrounding tissue in indirect ways.